Therapeutic effervescent compositions

ABSTRACT

Granulates comprising an effervescent couple of anhydrous powdered monosodium citrate and powdered sodium bicarbonate and prepared using a roller compactor are formulated into pharmaceutical compositions.

This application is a 371 of PCT/EP96/02934 filed Jun. 28, 1996.

This invention relates to novel granulates comprising effervescentcouples, pharmaceutical formulations comprising such granulates, toprocesses for the manufacture thereof and the use of such formulationsin therapy.

Effervescent pharmaceutical formulations are well known in the art. Atthe simplest level, such compositions include a couple which comprisesan acid such as citric acid or a mono or dihydrogen salt thereof and acarbon dioxide source such as a carbonate or hydrogen carbonate alkalimetal salt, such as sodium hydrogen carbonate. These do not reacttogether when dry but combine to release carbon dioxide and aneffervescent effect in the presence of water. The pharmaceuticalcompositions may be in the form of a tablet for dissolving in water or adispersible powder for sprinkling onto water, prior to administration.The components of the couple are blended together during manufacture ofthe composition. It is important to avoid water, to prevent prematureeffervescence. The latter, in the case of a citric acid or mono hydrogensalt/sodium hydrogen carbonate couple, leads to the formation of carbondioxide and may lead to additional and undesirable degradation when thedrug substance is acid sensitive.

A suitable drug for use in an effervescent formulation is cimetidine,marketed by Smith Kline & French Laboratories as Tagamet. Aneffervescent tablet preparation containing 200 mg cimetidine and acitric acid/sodium hvdrogen carbonate stoichiometric couple is marketedin several European countries. The couple is produced by a wetgranulation process. The effervescent formulation also helps to overcomethe bitter taste of cimetidine. In addition. EP 0 233 853-A(Laboratoires Smith Kline & French) describes effervescent couplesparticularly suitable for use with H₂ antagonists such as cimetidinewhich are sensitive to acid. The couple comprises a mixture of mono- anddialkali metal citrate salts in a defined ratio. This is prepared bypartially neutralising citric acid by treatment thereof with an alkalimetal carbonate or bicarbonate salt in water and stopping the reactionwhen a certain amount of carbon dioxide has been evolved. This processesinvolves several steps, including wet granulation and subsequent drying.A shorter, more efficient process would be commercially attractive.

We have now found that improved couples may be prepared more efficientlyif a dry Granulation technique involving a roller compactor is used toblend together the components of the couple. The use of a rollercompactor is becoming increasingly common in pharmaceutical technology.The technique depends upon the densification of a fine powder to obtainfragments or flakes of undefined shape. These flakes are then usuallycrushed to obtain granulates which are screened to the size required bythe user.

The use of roller compaction to prepare granulates comprising a sodiumhydrogen sulphate/sodium hydrogen carbonate couple, for subsequentincorporation into effervescent tablets for use in cleaning toiletbowls, is described in Pharmaceutical Dosage Forms: Tablets, vol 1, ed HA Lieberman and L Lachman (Marcel Dekkel, 1980).

Accordingly, the present invention provides for pharmaceuticalgranulates comprising an effervescent couple, characterised in that thecouple comprises anhydrous powdered monosodium citrate and powderedsodium bicarbonate and the granulates are prepared using a rollercompactor.

Such granulates are found to dissolve more quickly and more fully inwater and there is also no chemical reaction between the components.

The most effective granulates are made using anhydrous powderedmonosodium citrate of a certain particle size range. Suitable grades ofanhydrous powdered monosodium citrate comprise particles which aresubstantially (i.e. about more than 90%) within the range 0 to 500microns, preferably 355 microns, more preferably 0 to 250 microns.Suitable grades are available from Roche (monosodium citrate anhydrouspowder, maximum of 5% w/w with grain size >0.250 mm), BoehringerIngelheim (monosodium zilrate wasserfrei Art-Nr 661 511, minimum of 90%w/w with grain size <0.150 mm), Jungbunzlauer (maximum of 5% w/w withgrain size >0.355 mm) and Haarmann & Reimer Corp. (maximum of 1% withgrain size >0.500 mm).

Suitable grades of powdered sodium bicarbonate comprise particles whichare substantially (i.e. about more than 90%) within the range of 0 to500 microns, preferably 270 microns more preferably 0 to 130 microns.Suitable grades of powdered sodium bicarbonate are available fromSolvay, for instance the grades 0 to 13 (particle size, by sievingmethod: >0.16 mm max; 15 g/kg) and extra-fine (particle size by sievingmethod: >0.125 mm max; 20 g/kg).

Tablets manufactured using Granulates with low particle size were foundto be harder than those manufactured using granulates with largeparticle size but were otherwise comparable.

Granulates according to the present invention may be obtained by aprocess which comprises the steps of:

a) blending together the components of the couple;

b) roller compacting the blend to produce flakes;

c) crushing the flakes to obtain granulates; and

d) if desired, screening the granulates by size.

Suitably, the components of the couple are blended together at acontrolled temperature, for instance about 20° C. and controlledrelative humidity, for instance about 20% RH and processed in a rollercompactor to form flakes. Roller compaction may be carried out over arange of linear compaction strengths, the appropriate value beinginfluenced by the particle size of the monosodium citrate and sodiumhydrogen carbonate. For smaller particle sizes (for instance, the gradesof monosodium citrate from Boehringer Ingelheim and sodium hydrogencarbonate from Solvay previously mentioned), linear roller compactionstrengths of about 20 KN/cm are found to give suitable granulates forfurther processing into final finished forms such as tablets. For largerparticle sizes (for instance monosodium citrate from Jungbunzlauer),linear compaction strengths of about 30 KN/cm are preferred. The flakesthus obtained are then crushed to obtain granulates which are screenedto the size required for further processing, suitably a size in therange 0 to 1250 microns is used. Suitably the granulates thus obtainedare calibrated for effervescent potency using a standard assay, prior tofurther use.

Suitably, granulates according to the present invention are incorporatedinto a pharmaceutical formulation. Accordingly, in a further aspect, thepresent invention provides a pharmaceutical formulation comprisinggranulates comprising an effervescent couple and a drug substance whichmay optionally be incorporated into the Granulates, characterised inthat the couple comprises anhydrous powdered monosodium citrate andpowdered sodium bicarbonate and the granulates are processed using aroller compactor.

Suitably, granulates may comprise the components of the couple and,optionally, other pharmaceutically acceptable excipients and/or drugsubstance. Accordingly, in a further aspect, the present inventionprovides pharmaceutical formulations comprising Granulates comprising aneffervescent couple and a drug substance, characterised in that thecouple comprises anhydrous powdered monosodium citrate and powderedsodium bicarbonate and the granulates are prepared using a rollercompactor.

Suitable drug substances include H₂-antagonists well known in the artsuch as ranitidine, cimetidine, famotidine, nizatidine and roxatine orpharmaceutically acceptable salts thereof. A representative drugsubstance is cimetidine or the hydrochloride salt thereof. Othersuitable drug substances include those obtainable directly ‘over thecounter’ (OTC drugs) such as analgesics, for instance aspirin,ketoprofen, naproxen, paracetamol and ibuprofen. Other suitable productsin which such effervescent couples may be incorporated includeindigestion products, vitamin supplements and antibiotics.

Suitably, the drug substance is incorporated in an amount such thatindividual tablets comprise unit dosages of the particular medicament,for instance 200 mg of cimetidine or 500 mg of paracetamol.

Suitable pharmaceutical formulations include effervescent tablets andsachets containing water dispersible powders. Pharmaceuticalformulations according to the present invention may be prepared bylending together the granulates formed by roller compaction with othercomponents prior to processing into final form. Roller compaction mayalso be extended to include other components, such as drug substance andexcipients such as lubricants, disintegrants, flavours and sweeteners.For tablets, final processing may include compressing into tablets usinga tabletting machine.

Preferably, monosodium citrate and sodium bicarbonate, as herein beforedefined, are blended together and then roller compacted, preferably inthe absence of water, to form flakes which are then crushed to givegranulates. The granulates thus obtained may then be combined with druosubstance, for instance cimetidine (or the hydrochloride salt thereof),conventional tabletting or filling agents and, optionally, sweeteners,flavours and lubricants and compressed or filled together, suitablyunder controlled ambient conditions, to form tablets or sachets,respectively. Suitable tablets will have a hardness in the range 6 to 12Kp. The hardness of the final tablets is found to be influenced by thelinear roller compaction strength used in preparing the granulates.Suitable linear compaction strengths are in turn influenced by theparticle size of the monosodium hydrogen carbonate and sodium hvdrogencarbonate. For smaller particle sizes (for instance the grades ofmonosodium citrate from Boehringer Ingelheim and sodium hydrogencarbonate from Solvay previously mentioned) a linear roller compactionstrength of about 20 KN/cm is preferred. Higher linear compactionstrengths are found to granulates which when incorporated into tabletsgive harder tablets (up to 17 Kp). At a linear compaction strength ofless than 16 KN/cm, subsequent tablets are found to be very soft. Forlarger particle sizes (for instance monosodium citrate fromJungbunzlauer), a linear compaction strenoth of about 30 KN/cm ispreferred. Tablets comprising cimetidine show no cimetidine degradationproblems after storage for 2 months at 40° C.

In addition, drug substance, for instance cimetidine, may also beblended together with the components of the couple and the mixture thensubjected to roller compaction, followed by crushing to give granulates.These granulates may then be blended together with sweeteners, flavoursand lubricants and then compressed into tablets. The sweeteners andflavours may also be incorporated into the initial blend, for rollercompaction.

Suitable sweeteners are well known in the art and include aspartame,sodium saccharin, acesulfame potassium and sodium cyclamate.

Suitable lubricants are well known in the art and include PEG 6000,sodium benzoate and dimethicone.

The formulations of the present invention may also include additionalexcipients and agents well known in the art, for instance disintegrants,wetting agents and colouring agents.

Pharmaceutical formulations according to the present invention are ofuse in therapy according to the identity of the drug substance containedtherein. Accordingly, in a further aspect, the present inventionprovides for a pharmaceutical formulation herein before defined for usein therapy. The present invention also provides for the use of a coupleas herein before defined in the manufacture of a medicament for use intherapy. Such pharmaceutical formulations containing an H₂-antagonistsuch as cimetidine are of use in the treatment of duodenal, gastric,recurrent and stomach ulcerating reflux oesophagitis, and in themanagement of patients who are at high risk from haemorrhage of theupper gastro-intestinal tract.

The invention will now be illustrated by the following example.

EXAMPLE 1

‘200 mg’ effervescent tablet comprising cimetidine

1. Stoichiometric Roller Compacted Effervescent Granules

Anhydrous powdered monosodium citrate (ex B Ingelheim) 1426.2 g PowderedSodium bicarbonate (ex Solvay) 1118.8

The ingredients were blended to-ether and subjected to roller compactionat a linear compaction strength of 20 KN/cm at 20-25° C. and about20%RH. The flakes were then crushed and size-sorted by sieving to givegranulates for use in tablet formulation.

2. Tablet

w/w Stoichiometric roller compacted effervescent granulates 2,545 gCimetidine base 200.0 Flavours 27.5 Aspartame 15.0 Saccharin Sodium 8.0PEG 6000 20.0 Sodium benzoate 100.0

The above ingredients, suitably scaled up, were blended together in amixing device at 20-25° C. and about 20% RH and the resultant blendtabletted on a rotative press fitted with 22 mm punches. This gave flatround tablets weighing 2915.5 mg with a hardness about 6 to 12 Kp whichdissolved in 45 to 75 s in water at 20° C.

EXAMPLE 2

‘500 mg’ effervescent tablet comprising paracetamol

1. Stoichiometric Roller Compacted Effervescent Granules

Anhydrous powdered monosodium citrate (ex Jungbunzlauer) 1426.2 gPowdered sodium bicarbonate 0/13 (ex Solvay) 1118.8

The ingredient were blended together and subjected to roller compactionat a linear compaction strength of 30 KN/cm at 20-25° C. and about 20%RH. The flakes were then crushed and size-sorted by sieving through a1.25 mm screen to give granulates for use in tablet formulation.

2. Tablet

(w/w) Stoichiometric roller compacted effervescent granules 1840.0 mgParacetamol (powdered) 500.0 mg Sorbitol 400.0 mg PEG 6000 100.0 mgPolysorbate 80 3.0 mg Sodium saccharinate 8.0 mg (TOTAL 2851.0 mg)

The polvsorbate was mixed with a part of sorbitol to give an homogeneousdry mixing.

After the above mixing, the remaining sorbitol and other components wereblended together in a mixing device at 20-25° C. and about 20% RH. Theresultant blend was tabletted on a press fitted with 20mm punches.

The tablets obtained showed following characteristics:

weight 2851 mg thickness about 4.48 mm dissolution time about 45 s

What is claimed is:
 1. A process for preparing pharmaceutical granulatescomprising an effervescent couple which process comprises the steps of:a) blending together the components of the couple, which are anhydrouspowdered monosodium citrate and powdered sodium bicarbonate; b) rollercompacting the blend to produce flakes; c) crushing the flakes to obtaingranulates; and d) if necessary and so desired, screening the granulatesby size.
 2. The pharmaceutical granulates produced according to claim 1which further comprise a drug substance incorporated into thegranulates.
 3. The pharmaceutical granulates produced according to claim1 in which the anhydrous powdered monosodium citrate particles used aresubstantially within the size range less than 500 microns.
 4. Thepharmaceutical granulates produced according to claim 3 in which theanhydrous powdered monosodium citrate particles used are substantiallywithin the size range less than 355 microns.
 5. The pharmaceuticalgranulates produced according to claim 4 in which the anhydrous powderedmonosodium citrate particles used are substantially within the sizerange less than 250 microns.
 6. The pharmaceutical granulates producedaccording to claim 1 in which the powdered sodium bicarbonate particlesused are substantially within the size range less than 500 microns. 7.The pharmaceutical granulates produced according to claim 6 in which thepowdered sodium bicarbonate particles used are substantially within thesize range less than 270 microns.
 8. The pharmaceutical granulatesproduced according to claim 7 in which the powdered sodium bicarbonateparticles used are substantially within the size range less than 130microns.
 9. The pharmaceutical granulates produced according to claim 2in which the drug substance in an H₂-antagonist or an analgesic.
 10. Apharmaceutical formulation comprising granulates which comprise aneffervescent couple, and a drug substance incorporated into thegranulates, in which the couple comprises anhydrous powdered monosodiumcitrate and powdered sodium bicarbonate; and wherein the drug substanceis cimetidine, or the hydrochloride salt thereof, or paracetamol, andwherein the granulates are prepared using a roller compactor.
 11. Thepharmaceutical granulates according to claim 2 which are furthercompressed into a tablet or further formulated as a water dispersiblepowder.
 12. A process for preparing pharmaceutical granulates whichgranulates comprising an effervescent couple and a drug substance, andwherein the couple comprises anhydrous powdered monosodium citrate, andpowdered sodium bicarbonate, which process comprises the steps of: a)blending together the components of the couple; b) roller compacting theblend to produce flakes; c) crushing the flakes to obtain granulates;and d) if necessary and so desired, screening the granulates by size; e)adding to the flakes of step (c) or (d) a drug substance.
 13. Thepharmaceutical formulation according to claim 10 wherein the cimetidineor hydrochloride salt thereof is incorporated in to the granulates afterthe effervescent couple has been roller compacted.
 14. Thepharmaceutical granulates according to claim 2 wherein the drugsubstance is incorporated into the granules after the effervescentcouple has been roller compacted.
 15. A pharmaceutical formulationaccording to claim 9 in the form of a tablet or a water dispersiblepowder.
 16. The process according to claim 12, which process furthercomprises admixing the components of step (a), the granulates of step(c) or step (e) with additional excipients.
 17. The process according toclaim 16 wherein the drug substance is an H₂-antagonist or an analgesic.18. The process according to claim 17 wherein the H₂-antagonist iscimetidine, or the hydrochloride salt thereof, and the analgesic isparacetamol.
 19. The process according to claim 16 wherein thegranulates have particles which are substantially less than 500 micronsin size.
 20. The process according to claim 19 wherein the granulateshave particles which are substantially less than 270 microns in size.21. A pharmaceutical formulation comprising granulates according toclaim 16, in the form of a tablet or sachet.